CN104211734A - Novel synthetic method of antitumor drug heptyl platinum - Google Patents
Novel synthetic method of antitumor drug heptyl platinum Download PDFInfo
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- CN104211734A CN104211734A CN201410389065.XA CN201410389065A CN104211734A CN 104211734 A CN104211734 A CN 104211734A CN 201410389065 A CN201410389065 A CN 201410389065A CN 104211734 A CN104211734 A CN 104211734A
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- aminomethyl
- eptaplatin
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- propyl
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Abstract
The invention relates to a preparation method of an antitumor drug heptyl platinum. A process is as below: reacting a starting material K4PtCl4 with sodium nitrite to generate a K4Pt (NO2)4 solution, reacting with (4R,5R)-4,5-bis (aminomethyl)-2-isopropyl-1,3-dioxolane to form cis-dinitroso-(4R,5R)-4,5-bis (aminomethyl)-2-isopropyl-1,3- dioxolane platinum (II), reducing NO2- radical by using hydrazine nitrate, and reacting the obtained solution with malonic acid solution in the pH value of about 7-8 to generate heptyl platinum. The method does not introduce silver ion and has yield at about 80%.
Description
Technical field
The present invention relates to the preparation of platinum series antineoplastic medicament Eptaplatin, belong to field of pharmaceutical chemistry technology.
Background technology
Platinum series antineoplastic medicament with its significant curative effect, is widely used in clinical in oncotherapy, and becomes the important component part in many tumour scheme of combination drug therapy.The wider platinum medicine of current domestic application is carboplatin, cis-platinum, oxaliplatin.Domestic enterprise now again visual cognitive ability in the exploitation of Eptaplatin.Eptaplatin (Heptaplatin) is the exploitation of Sunkyong industries company of Korea S, and obtain korean foods drug administration (KFDA) approval first in Korean market in July, 1999, commodity are called Sunpla.Eptaplatin proves to exceed carboplatin, cis-platinum to the therapeutic action of cancer through clinical trial, can share with a series of cancer therapy drug.The indication that Sunpla ratifies the earliest is be used in conjunction the cancer of the stomach for late period, transitivity or recurrence after operation with 5 FU 5 fluorouracil, present indication is expanded as: be used for the treatment of small cell lung cancer, cancer of the stomach, cervical cancer and colorectal carcinoma, especially have good efficacy to cancer of the stomach, lung cancer etc.Eptaplatin not only antitumor action is strong, and side effect is little.According to the information that SK company announces, Sunpla adverse reaction rate is low and slight, alopecia and neurovirulent incidence are lower than 2%, incidence of vomiting is 3.3%, and the incidence of vomiting of other similar medicine is 36.5%, carboplatin and cis-platinum are all the cancer therapy drugs that height causes telling property, and lower incidence of vomiting not only increases the compliance of patient, and decreases medical expense.
Synthesis document (the CN1063753C of Eptaplatin, CN1629171A) main employing is the method that synthesizing cis platinum complex is conventional, namely potassium chloroplatinite successively with potassiumiodide and with (4R, 5R)-4, two (the aminomethyl)-2-sec.-propyl-1 of 5-, the reaction of 3-dioxolane alkane generates intermediate cis-diiodo--(4R, 5R)-4, two (the aminomethyl)-2-sec.-propyl-1 of 5-, 3-dioxolane alkane closes platinum (II), then with Silver Nitrate, Sulfuric acid disilver salt or silver suboxide etc. react filter after the hydrate that obtains and malonate react.Or intermediate is direct and silver-colored reaction of propanedioic acid generates target product.The hydrate that document (Chinese Journal of Inorganic Chemistry, 2004,20 (2), 215-218) replaces silver salt and intermediate to be hydrolyzed producing with corresponding Mercury protonitrate and malonate react and generate target product.Document (zl200610010609.2) adopts platinochloride and malonate reaction generation two (malonate) to close platinate, again with (4R, two (the aminomethyl)-2-sec.-propyl of 5R)-4,5--DOX alkane reaction generates Eptaplatin.
The synthetic method of the Eptaplatin of current bibliographical information mainly uses silver salt or mercury salt in building-up process, easily causes precious metal impurity to exceed standard, and affects the quality of medicine.
Summary of the invention
The object of the invention is for the deficiency of syntheti c route in above-mentioned prior art, provide a kind of preparation method of Eptaplatin, the method does not use silver or hydrargyrum complex, and route is short, easy and simple to handle.
Technical scheme of the present invention is as follows:
A preparation method for Eptaplatin, is characterized in that K
2ptCl
4react with Sodium Nitrite and generate K
2pt (NO
2)
4solution, again with (4R, 5R)-4, two (the aminomethyl)-2-sec.-propyl-1 of 5-, the reaction of 3-dioxolane alkane generates two (the aminomethyl)-2-sec.-propyl-1 of cis-dinitroso-(4R, 5R)-4,5-, 3-dioxolane alkane closes platinum (II), uses hydrazine nitrate reductive NO
2 -the solution obtained after root and propanedioic acid solution are about to react between 7-8 in pH value and generate Eptaplatin.
Chemical reaction flow process of the present invention is:
Eptaplatin synthetic method of the present invention is compared with the method for above-mentioned bibliographical information, high, with short production cycle, the applicable scale operation of yield and effectively control Ag
+ion.
Embodiment
The reagent that invention adopts and material
1.K
2ptCl
4for Kunming Guiyan Pharmaceutical Co., Ltd.'s preparation, purity >98%.
2. Sodium Nitrite, (4R, 5R)-4,5-pairs of (aminomethyl)-2-sec.-propyl-DOX alkane, hydrazine nitrate, propanedioic acid, sodium hydroxide and dehydrated alcohols are commercially available analytical pure.
The present invention is further illustrated below by example.Example of the present invention is only used for the present invention being described and providing, and is not limitation of the present invention.So, under method prerequisite of the present invention, all protection scope of the present invention is belonged to simple modifications of the present invention.
Embodiment 1 takes potassium chloroplatinite 8.3g (20mmol) and dissolves by purified water, taking after Sodium Nitrite 6.9g (100mmol) purified water is dissolved joins in chloro-platinous acid potassium solution, at 60 DEG C, react 5h, after being filtered by a small amount of insolubles, obtain shallow yellow transparent solution.Take (4R, 5R)-4, two (the aminomethyl)-2-sec.-propyl-1 of 5-, 3-dioxolane alkane 3.48g (20mmol), be added drop-wise in shallow yellow transparent solution after dissolving by purified water, after at room temperature reacting 5h, the yellow mercury oxide obtained filtered, wash 3 times, after dehydrated alcohol washes 3 times, drying obtains 7.47g light yellow solid, productive rate 81%.
Take cis-dinitroso-(4R, 5R)-4, two (the aminomethyl)-2-sec.-propyl-1 of 5-, 3-dioxolane alkane closes platinum (II) 4.61g (10mmol), suspension liquid is stirred into by purified water, taking after hydrazine nitrate 4.74g (30mmol) purified water is dissolved joins in suspension liquid, reacts 4h and obtain shallow yellow transparent solution at 55 DEG C.Taking after propanedioic acid 2.08g (20mmol) purified water is dissolved joins in shallow yellow transparent solution, regulate with sodium hydroxide and keep pH value between 7-8, room temperature reaction 6h, by the solid filtering obtained, wash 3 times, after dehydrated alcohol washes 3 times, drying obtains 3.86g white solid, productive rate 82%.It is 99.5% that purity is analyzed through HPLC, and ultimate analysis C28.6%, H4.21%, N6.04%, Pt41.8% are consistent with theoretical value, MS-ESI
+494, [M+Na], IR (KBr compressing tablet) and
1hNMR (DMSO, ppm) is all consistent with document (J.Med.Chem., 1994,37,1471-1485).
Embodiment 2 takes potassium chloroplatinite 8.3g (20mmol) and dissolves by purified water, taking after Sodium Nitrite 6.21g (90mmol) purified water is dissolved joins in chloro-platinous acid potassium solution, at 55 DEG C, react 4h, after being filtered by a small amount of insolubles, obtain shallow yellow transparent solution.Take (4R, 5R)-4, two (the aminomethyl)-2-sec.-propyl-1 of 5-, 3-dioxolane alkane 5.22g (30mmol), be added drop-wise in shallow yellow transparent solution after dissolving by purified water, after at room temperature reacting 5h, the yellow mercury oxide obtained filtered, wash 3 times, after dehydrated alcohol washes 3 times, drying obtains 7.84g light yellow solid, productive rate 85%.
Take cis-dinitroso-(4R, 5R)-4, two (the aminomethyl)-2-sec.-propyl-1 of 5-, 3-dioxolane alkane closes platinum (II) 4.61g (10mmol), suspension liquid is stirred into by purified water, taking after hydrazine nitrate 3.95g (25mmol) purified water is dissolved joins in suspension liquid, reacts 4h and obtain shallow yellow transparent solution at 55 DEG C.Taking after propanedioic acid 2.08g (20mmol) purified water is dissolved joins in strong yellow transparent solution, regulate with sodium hydroxide and keep pH value between 7-8, room temperature reaction 6h, by the solid filtering obtained, wash 3 times, after dehydrated alcohol washes 3 times, drying obtains 3.81g white solid, productive rate 81%.It is 99.7% that purity is analyzed through HPLC.
Embodiment 3 takes potassium chloroplatinite 8.3g (20mmol) and dissolves by purified water, taking after Sodium Nitrite 7.59g (110mmol) purified water is dissolved joins in chloro-platinous acid potassium solution, at 55 DEG C, react 4h, after being filtered by a small amount of insolubles, obtain shallow yellow transparent solution.Take (4R, 5R)-4, two (the aminomethyl)-2-sec.-propyl-1 of 5-, 3-dioxolane alkane 5.22g (30mmol), be added drop-wise in shallow yellow transparent solution after dissolving by purified water, after at room temperature reacting 5h, the yellow mercury oxide obtained filtered, wash 3 times, after dehydrated alcohol washes 3 times, drying obtains 7.84g light yellow solid, productive rate 85%.
Take cis-dinitroso-(4R, 5R)-4, two (the aminomethyl)-2-sec.-propyl-1 of 5-, 3-dioxolane alkane closes platinum (II) 4.61g (10mmol), suspension liquid is stirred into by purified water, taking after hydrazine nitrate 3.16g (20mmol) purified water is dissolved joins in suspension liquid, reacts 4h and obtain shallow yellow transparent solution at 55 DEG C.Taking after propanedioic acid 2.08g (20mmol) purified water is dissolved joins in shallow yellow transparent solution, regulate with sodium hydroxide and keep pH value between 7-8, room temperature reaction 7h, by the solid filtering obtained, wash 3 times, after dehydrated alcohol washes 3 times, drying obtains 3.95g white solid, productive rate 84%.It is 99.4% that purity is analyzed through HPLC.
Claims (5)
1. a preparation method for Eptaplatin, is characterized in that K
2ptCl
4react with Sodium Nitrite and generate K
2pt (NO
2)
4solution, again with (4R, 5R)-4, two (the aminomethyl)-2-sec.-propyl-1 of 5-, the reaction of 3-dioxolane alkane generates two (the aminomethyl)-2-sec.-propyl-1 of cis-dinitroso-(4R, 5R)-4,5-, 3-dioxolane alkane closes platinum (II), uses hydrazine nitrate reductive NO
2 -the solution obtained after root and propanedioic acid solution are about to react between 7-8 in pH value and generate Eptaplatin.
2. Eptaplatin preparation method as claimed in claim 1, is characterized in that: described K
2ptCl
4be 1:4 ~ 6 with the ratio of the amount of substance of Sodium Nitrite, temperature of reaction is 50-75 DEG C, and the time is 4 ~ 8h.
3. Eptaplatin preparation method as claimed in claim 1, is characterized in that: (4R, 5R)-4,5-pairs of (aminomethyl)-2-sec.-propyl-DOX alkane and K
2ptCl
4the ratio of amount of substance be 1 ~ 2:1, (4R, 5R)-4,5-two (aminomethyl)-2-sec.-propyl-DOX alkane and K
2pt (NO
2)
4the temperature of solution reaction is room temperature, and the reaction times is 4 ~ 8h.
4. Eptaplatin preparation method as claimed in claim 1, it is characterized in that: hydrazine nitrate and cis-dinitroso-(4R, 5R)-4, two (the aminomethyl)-2-sec.-propyl-1 of 5-, the ratio that 3-dioxolane alkane closes the amount of substance of platinum (II) is react 2 ~ 6h at 2 ~ 5:1,30-60 DEG C.
5. Eptaplatin preparation method as claimed in claim 1, it is characterized in that propanedioic acid and cis-dinitroso-(4R, 5R)-4, two (the aminomethyl)-2-sec.-propyl-1 of 5-, the ratio that 3-dioxolane alkane closes the amount of substance of platinum (II) is 1 ~ 5:1, pH value is between 7-8, and temperature of reaction is room temperature, and the time is 5 ~ 10h.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0193936B1 (en) * | 1985-03-06 | 1989-05-31 | Sumitomo Pharmaceuticals Company, Limited | Liposoluble platinum (ii) complex and preparation thereof |
| JPH11315088A (en) * | 1998-03-06 | 1999-11-16 | Sumitomo Pharmaceut Co Ltd | Fat soluble platinum (ii) complex hydrate |
| CN1629171A (en) * | 2004-10-22 | 2005-06-22 | 北京双鹭药业股份有限公司 | Novel sunplatinum preparation and its preparation process |
| CN102766169A (en) * | 2012-08-01 | 2012-11-07 | 昆明贵研药业有限公司 | New method for synthesizing anti-tumor drug miboplatin |
-
2014
- 2014-08-10 CN CN201410389065.XA patent/CN104211734A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0193936B1 (en) * | 1985-03-06 | 1989-05-31 | Sumitomo Pharmaceuticals Company, Limited | Liposoluble platinum (ii) complex and preparation thereof |
| JPH11315088A (en) * | 1998-03-06 | 1999-11-16 | Sumitomo Pharmaceut Co Ltd | Fat soluble platinum (ii) complex hydrate |
| CN1629171A (en) * | 2004-10-22 | 2005-06-22 | 北京双鹭药业股份有限公司 | Novel sunplatinum preparation and its preparation process |
| CN102766169A (en) * | 2012-08-01 | 2012-11-07 | 昆明贵研药业有限公司 | New method for synthesizing anti-tumor drug miboplatin |
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Application publication date: 20141217 |